The Human Immunodeficiency Virus (HIV) has now been established as the causative agent of the Acquired Immunodeficiency Syndrome (AIDS) for over 20 years (Science 1983, 220, 868-871; N. Eng. J. Med. 1984, 311, 1292-1297). AIDS is characterized by the destruction of the immune system, particularly of CD4+T-cells. HIV is a retrovirus, and the HIV life cycle encompasses several crucial steps, starting from the attachment of the virus to the host cell membrane and finishing with the release of progeny virons from the cell.
The natural compound betulinic acid, isolated from Syzygium clavifolium and several other plant species was found to possess anti-HIV activity. Chemical modifications were undertaken by several research groups in an attempt to identify potent anti-HIV agents by making semi-synthetic analogs of betulinic acid, leading to the discovery of Bevirimat as a compound with a novel mechanism of action (J. Nat. Prod. 1994, 57(2): 243-7; J. Med. Chem. 1996, 39(5), 1016). Further studies shown that Bevirimat acts by disrupting Gag processing (Proc. Natl. Acad. Sci. USA 2003, 100 (23):13555-60; Antimicrob. Agents. Chemother. 2001, 45(4), 1225-30; J. Virol. 2004, 78(2): 922-9; J. Biol. Chem. 2005, 280(51): 42149-55; J. Virol. 2006, 80(12): 5716-22) and to be a first-in-class maturation inhibitor with a potent activity against HIV-1. Bevirimat went up to phase 2 clinical trials, in clinic despite optimal plasma concentrations, not all patients given bevirimat have a robust viral load reduction. It was reported that non-respondant patients had more frequent base line Gag polymorphisms near the capsid SP-1 cleavage site than responders. (HIV gag polymorphism determines treatment response to bevirimat. XVII international HIV drug resistance work shop Jun. 10-14, 2008, Sitges, Spain).
Encouraged by these developments, medicinal chemists started exploring betulinic acid derivatives and related compounds intensively for their therapeutic activities. For example, WO 2014/105926 disclosed novel betulinic acid proline derivatives as HIV inhibitors; WO 2013/160810 disclosed novel betulinic acid derivatives as HIV inhibitors; WO 2011/007230 describes preparation of lupeol-type triterpene derivatives as antiviral agents; WO 2014/093941 describers pharmaceutical compositions of betulin derivatives; WO 2009/082819 describes preparation of 17-amino lupane derivatives as anti-HIV agents; WO 2013/020245 describes carbonyl derivatives of betulin; WO 2009/082818 describes preparation of C21-keto lupane derivatives for the treatment of HIV Infections; WO 2011/100308 describes preparation of betulin derivatives for treatment of HIV-1; WO 2013/090664 describes preparation of betulin derivatives for the treatment of HIV; WO 2013/117137 describes lupane triterpenoids derivatives and pharmaceutical use thereof; WO 2013/091144 describes preparation of propenoate derivatives of betulin useful for the treatment of HIV.
Some additional references disclose betulinic acid related compounds. For example, WO 2013/090683 describes preparation of betulin propenoate derivatives for the treatment of HIV; WO 2013/020246 describes preparation of methylene derivatives of betulin useful for the treatment of HIV; WO 2010/132334 describes C3,28-Disubstituted betulinic acid derivatives as Anti-HIV agents; US 2011/0152229 describes betulinic acid derivatives as anti-HIV agents; WO 2008/057420 describes extended triterpene derivatives as antiretroviral agents; WO 2013/123019 describes C-3 cycloalkenyl triterpenoids with HIV maturation inhibitory activity; WO 2007/141392 describes compositions comprising betulonic acid; WO 2007/141391 describes betulin derived compounds useful as antiprotozoal agents; WO 2007/141390 describes preparation of betulin derived compounds as antiviral agents; WO 2007/141389 describes preparation of betulin derived compounds as antibacterial agents.
Given the fact of the world wide epidemic level of AIDS, there is a strong continued need for new effective drugs for treatment of HIV infected patients, disease conditions and/or disorders mediated by HIV by discovering new compounds with novel structures and/or mechanism of action(s).